The cellular growth of normal tissue is maintained in homeostasis. This balance is determined by cellular proliferation and renewal on one hand, and cell death on the other. Neoplasia can result from aberrant regulation of this homeostasis, through somatic genetic abnormalities that cause cancer initiation and progression. One approach to tumor therapy is to determine agents that act to initiate programmed cell death, or apoptosis. Apoptosis is a form of cell suicide that is critical for differentiation during embryogenesis and regulation of cell numbers. It can also be induced in neoplastic cells, so that they self-destruct. A growing body of evidence suggests that the intracellular "death program" activated during apoptosis is similar in different cell types and conserved during evolution.
Apoptosis involves two essential steps. The Bcl-2 family of proteins that consists of different anti- and pro-apoptotic members is important in the "decision" step of apoptosis. In contrast, the "execution" phase of apoptosis is mediated by the activation of caspases, cysteine proteases that induce cell death via the proteolytic cleavage of substrates vital for cellular homeostasis. Bcl-2-related proteins act upstream from caspases in the cell death pathway.
Tumor necrosis factor (TNF) is the prototypic member of a family of cytokines, which interact with their receptors to carry out diverse functions. Some TNF-receptor family members, termed the "death receptors", which comprise a "death domain", have the unique ability to transmit an intracellular death signal. These receptors include TNF-R1, Fas (CD95), TRAMP (wsl/Apo-3/DR-3), TRAIL-R1 (DR-4) and TRAIL-R2 (DR-5, TRICK2, KILLER). The ligands for these receptors are capable of inducing apoptosis in tumor cells. However, the potential utility of systemically administered TNF, Fas ligand or lymphotoxin has been limited by their acute toxic effects on normal tissues in vivo.
Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Tumor necrosis factor-.alpha. (TNF-.alpha.), for example, shows broad cytotoxicity against many tumor cell lines but its clinical use is limited because it induces a profound inflammatory response through activation of NF-.kappa.B. Moreover, activation of NF-.kappa.B inhibits TNF-.alpha.-induced apoptosis.
Many cancer cell lines are sensitive to the cytotoxic effects of TRAIL whereas most normal, non-transformed cells are resistant. Walczak et al. (1999) Nature Medicine 5:157-163, fused the receptor-binding region of TRAIL to a leucine zipper motif that favors trimerization. Trimers of leucine zipper TRAIL efficiently killed cultured mammary adenocarcinoma cells but not normal, non-transformed mammary epithelial cells. Systemic administration was able to enhance survival of animals when challenged with this tumor cell line, without detectable adverse effects on viability, tissue integrity, or red and white blood cell counts. The tumoricidal effect of TRAIL was shown to be due to the rapid induction of tumor cell apoptosis.
Strategies to treat tumors with this family of proteins are of great interest. It may be possible to `sensitize` resistant tumors to apoptosis, for example by modulating the expression or function of FLIP, which blocks the activity of caspases. Other strategies that have been suggested include manipulation of p53 expression. Methods of sensitization may permit the use of lower levels of the proteins, thereby reducing side effects. It may also permit the treatment of otherwise resistant tumors. Approximately 50% of the tumors tested have been resistant to killing by TRAIL (Griffith & Lynch (1998) Curr. Opin. Immunol. 10:559-563).
Relevant Literature
A review of the TNF receptor superfamily may be found in Baker and Reddy (1998) Oncogene 17(25): 3261-70. The tumor necrosis factor receptor (TNFR) superfamily represents a growing family, with over 20 members having been identified thus far in mammalian cells. These proteins share significant homologies in their extracellular ligand binding domains and intracellular effector (death) domains. Death signals seem to be associated with the activation of both the caspase and JUN kinase pathways. Gravestein and Borst (1998) Semin Immunol 10(6): 423-34 also review this receptor superfamily. The use of TRAIL as an anti-tumor agent is discussed in Walczak et al. (1999) Nature Medicine 5:157-163.
Yang et al. (1998) Immunopharmacology 40(2): 139-49 provide evidence that suggests the immunosuppressive agent triptolide inhibits antigen or mitogen-induced T cell proliferation, and induces apoptotic death of T cell hybridomas and peripheral T cells. Shamon et al. (1997) Cancer Lett 112(1): 113-7 evaluate the antitumor potential of triptolide.
The isolation, purification, and characterization of immunosuppressive compounds from tripterygium: triptolide and tripdiolide is reported by Gu et al. (1995) Int J Immunopharmacol 17(5): 351-6.